CN1446085A - 治疗绝经期或绝经后妇女更年期紊乱的方法 - Google Patents
治疗绝经期或绝经后妇女更年期紊乱的方法 Download PDFInfo
- Publication number
- CN1446085A CN1446085A CN01813019A CN01813019A CN1446085A CN 1446085 A CN1446085 A CN 1446085A CN 01813019 A CN01813019 A CN 01813019A CN 01813019 A CN01813019 A CN 01813019A CN 1446085 A CN1446085 A CN 1446085A
- Authority
- CN
- China
- Prior art keywords
- estrogen
- menopause
- treatment
- ester
- day
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000009245 menopause Effects 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 201000001880 Sexual dysfunction Diseases 0.000 claims abstract description 11
- 231100000872 sexual dysfunction Toxicity 0.000 claims abstract description 11
- 150000002148 esters Chemical class 0.000 claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 10
- 239000002207 metabolite Substances 0.000 claims abstract description 9
- 210000001215 vagina Anatomy 0.000 claims description 22
- 230000003203 everyday effect Effects 0.000 claims description 20
- 238000001035 drying Methods 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims 1
- LUMKNAVTFCDUIE-VHXPQNKSSA-N ospemifene Chemical compound C1=CC(OCCO)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 LUMKNAVTFCDUIE-VHXPQNKSSA-N 0.000 abstract description 43
- 206010047791 Vulvovaginal dryness Diseases 0.000 abstract 1
- 229960003969 ospemifene Drugs 0.000 description 39
- 239000000262 estrogen Substances 0.000 description 26
- 229940011871 estrogen Drugs 0.000 description 26
- 230000000694 effects Effects 0.000 description 24
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 16
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 14
- 229960004622 raloxifene Drugs 0.000 description 14
- 239000000328 estrogen antagonist Substances 0.000 description 12
- 230000001568 sexual effect Effects 0.000 description 11
- 206010006187 Breast cancer Diseases 0.000 description 9
- 208000026310 Breast neoplasm Diseases 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 9
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 230000009471 action Effects 0.000 description 7
- 230000001833 anti-estrogenic effect Effects 0.000 description 7
- 210000004696 endometrium Anatomy 0.000 description 7
- 230000001076 estrogenic effect Effects 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 229960001603 tamoxifen Drugs 0.000 description 7
- 201000008275 breast carcinoma Diseases 0.000 description 6
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 5
- 229940046836 anti-estrogen Drugs 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 229960005309 estradiol Drugs 0.000 description 5
- 229930182833 estradiol Natural products 0.000 description 5
- 229940088597 hormone Drugs 0.000 description 5
- 239000005556 hormone Substances 0.000 description 5
- 208000001132 Osteoporosis Diseases 0.000 description 4
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 4
- 230000002357 endometrial effect Effects 0.000 description 4
- 230000035800 maturation Effects 0.000 description 4
- 238000009595 pap smear Methods 0.000 description 4
- 208000035150 Hypercholesterolemia Diseases 0.000 description 3
- 238000008214 LDL Cholesterol Methods 0.000 description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 210000000981 epithelium Anatomy 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 210000004291 uterus Anatomy 0.000 description 3
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- 208000007415 Anhedonia Diseases 0.000 description 2
- 206010014759 Endometrial neoplasm Diseases 0.000 description 2
- 206010027304 Menopausal symptoms Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 201000003914 endometrial carcinoma Diseases 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 210000001711 oxyntic cell Anatomy 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 208000012201 sexual and gender identity disease Diseases 0.000 description 2
- 230000009329 sexual behaviour Effects 0.000 description 2
- 208000015891 sexual disease Diseases 0.000 description 2
- 229960003604 testosterone Drugs 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000003870 2-(1-piperidinyl)ethoxy group Chemical group [*]OC([H])([H])C([H])([H])N1C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- 241000194016 Bryanthus Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 208000004483 Dyspareunia Diseases 0.000 description 1
- 241000287227 Fringillidae Species 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030247 Oestrogen deficiency Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000020244 animal milk Nutrition 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 208000013219 diaphoresis Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- 108010038795 estrogen receptors Proteins 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 230000001965 increasing effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000002356 skeleton Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 208000020544 urinary system symptom Diseases 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/075—Ethers or acetals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/30—Oestrogens
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Gynecology & Obstetrics (AREA)
- Diabetes (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及绝经期或绝经后妇女阴道干燥或性功能障碍的治疗方法，所述方法包括给予妇女有效量的本发明的化合物(脱氨基羟基)托米芬或其可药用盐或酯，或其代谢物。
Description
发明领域
本发明涉及更年期紊乱，即绝经期或绝经后妇女阴道干燥或性功能障碍的治疗方法。
发明背景
在此使用的出版物和其他资料用于阐明本发明的发明背景，特别是提供关于实践的额外细节的例子，在此引入作为参考。
绝经期和绝经期后的妇女由于雌激素不足通常会出现一些症状。这些症状包括：潮热、发汗、失眠、抑郁、阴道干燥、尿失禁、恶心、疼痛、骨质疏松、冠心病、乳腺触痛、水肿、疲劳、性活动减少，以及并发的社会心理问题(Payer，1990；Rekers，1990)。此外，雌激素被认为有保护神经的作用。因而，老年女性逐渐降低的雌激素浓度可能对他们的智力活动有负面影响(Schneider & Finch，1997；Wickelgren，1997)。已知雌二醇在更年期症状治疗方面效果极佳，并且它在治疗以上症状方面的应用正迅速增加。然而，雌二醇导致子宫内膜癌和乳腺癌发生的风险增加。通过序贯服用孕激素而降低子宫内膜癌发生的风险是可行的，但是孕激素却无法降低乳腺癌发生的风险。尽管出于雌激素对骨骼、心血管系统、中枢神经系统的保护作用和缓解泌尿系统症状，继续长期地采用雌激素替代疗法是非常有用的，但致癌风险性限制了雌激素替代疗法的长期使用。
现常称为“选择性雌激素受体调节剂(SERM)”的抗雌激素药物具备雌激素样与抗雌激素的双重特性(Kauffman & Bryant，1995)。他莫昔芬和托米芬的该作用可能是组织特异性的，它们在骨中有雌激素样作用，在子宫和肝脏有部分雌激素样作用，在乳腺癌中有纯抗雌激素作用。雷洛昔芬和屈洛昔芬与他莫昔芬和托米芬相似，但它们的抗雌激素特性是主要的。依据已公开发表的信息，所有的SERM更可能引起更年期症状，而不是预防这些症状的发生。但它们对老年妇女有其他重要好处：它们通过降低总胆固醇与LDL胆固醇而降低绝经后妇女心血管疾病发生的风险，以及预防绝经后妇女骨质疏松和抑制乳腺癌生长。目前也正在研究几乎纯的抗雌激素药物。它们的主要针对乳腺癌的治疗(Wakeling & Bowler，1988)。
化合物(脱氨基羟基)托米芬，也已知其代码为FC-1271a，在经典的激素试验中具有相对弱的雌激素和抗雄激素作用(Kangas，1990)。它具有抗骨质疏松作用，并且它在实验模型和人类志愿者中降低总胆固醇和LDL胆固醇水平(国际专利公开WO 96/07402和WO97/32574)。它在动物乳腺癌模型中在乳腺癌发展的早期阶段具有抗肿瘤活性。抗雌激素药物对更年期症状的作用以前还没有研究过。FC-1271a是第一个已被证明对健康妇女的年龄相关症状具有有益作用的SERM。
发明概述
本发明涉及绝经期或绝经后阴道干燥或性功能障碍的治疗方法，所述方法包括给予妇女有效量的化合物(脱氨基羟基)托米芬或其可药用盐或酯，或其代谢物。
附图简述
图1A-1D表示每日用30mg FC-1271a(1A)，60mg FC-1271a(1B)，90mg FC-1271a(1C)，和60mg雷洛昔芬(1D)治疗的个体的阴道上皮表面细胞的核固缩指数。
图2表示每日剂量为30mg，60mg和90mg的FC-1271a和雷洛昔芬(每日剂量为60mg)对病人主观估计的阴道干燥的作用。
发明详述
本发明涉及雌激素受体调节剂FC-1271a，即(脱氨基羟基)托米芬在患有阴道干燥或性功能障碍的老年妇女中的用途。FC-1271a是托米芬的一种主要代谢物，已知它是一种雌激素激动剂和拮抗剂(Kangas，1990；国际专利申请WO 96/07402和WO 97/32574)。
FC-1271a(或(脱氨基羟基)托米芬)的结构式为
应该理解，该化合物也包括其几何异构体和立体异构体。
应该理解，“代谢物”包括任何已经发现或将发现的(脱氨基羟基)托米芬的代谢物。这些代谢物的例子包括Kangas(1990)在第9页提到的(TORE VI，TORE VII，TORE XVIII，TORE VIII，TORE XIII)，特别是TORE VI和TORE XVIII，以及该化合物的其它代谢物。
在一项临床研究中发现了该化合物的新的和令人惊讶的作用。在该研究中，将不同剂量的雷洛昔芬(60mg/日)或FC-1271a给予老年女性志愿者，持续3个月。在每日30，60和90mg的剂量水平，观察到阴道干燥的显著减少。也报道了性活动的改善。这些特性在已知的选择性雌激素受体调节剂(SERMs)中是新的和独特的，并且表明剂量为每日25mg至略低于100mg，特别是每日30-90mg的FC-1271a可以成功用于缓解老年妇女的阴道干燥和性功能障碍。此外，与任何已知的抗雌激素药物或SERM相比，FC-1271a具有更强的雌激素和抗雌激素作用。
已经发现化合物FC-1271a减轻性功能障碍并且增加性活性。女性性功能障碍的类型和原因为1)需要障碍，2)冲动障碍，3)高潮障碍和4)性交痛。这些大多数是由于激素原因，特别是因为雌激素和睾丸酮浓度降低。阴道干燥是女性性功能障碍的主要原因，一般在绝经后雌激素浓度降低时发生。这一般导致性交疼痛，它将间接影响任何形式的性功能障碍，包括心理原因。在老年妇女中，阴道干燥通常是性活动减少的主要原因(Spector I P，Carey M P： Incidence andprevalence of sexual dysfunctions：a critical review of theempirical literature.Archives of Sexual Behaviour 19：389-408，1990)。
雌激素和睾丸酮可用于阴道干燥的药物治疗，纯抗雌激素药物如雷洛昔芬导致阴道干燥，这并不令人惊讶。因此，病人不满意导致性交痛的治疗，并将停止治疗。
该化合物可以通过各种途径给药，其中口服和经皮给药途径是最优选的。
适当的制剂形式包括例如，片剂、胶囊、颗粒、粉末、悬浮液、浆液和经皮药膏或凝胶。
实验
在55-69岁的绝经后健康女性志愿者中进行了I-II期临床研究，以研究FC-1271a对子宫内膜厚度、子宫内膜病理(通过Vuopala etal，1982描述的刮宫术进行活检)以及宫颈涂片的作用。也评估了耐受性和药代动力学。用雷洛昔芬(每日60mg)作为对照。以每日30，60和90mg的剂量口服FC-1271a。每个剂量水平有29名志愿者，雷洛昔芬组也是如此。以含有30，60或90mg FC-1271a的明胶胶囊的形式给予FC-1271a。采用Hitachi EUB-405仪器，通过超声评价子宫内膜的厚度。阴道上皮通过本领域技术人员已知的评估方法之一的核固缩指数进行评估。在此方法中，宫颈涂片的阴道比例估计为来自不同层的细胞数目的百分比：基底旁(parabasal)细胞层、中间细胞层、以及表面细胞层。可以通过向表面细胞比例的偏移观察到雌激素性。在绝经后妇女中，该比例通过接近于0，雌二醇治疗使该比例增加至近100。在治疗前和治疗后(3个月时)取样。
也通过肉眼类似标准评估阴道干燥症状，其中志愿者自己记录她们主观的估计。该标准是基于纸上的一条100mm的线。左端代表无症状，右端是最差的可能症状。评估从治疗前至3个月时的改变的估计值，认为这可以指示疗效。
在任何治疗前测量中，各治疗组的统计数据之间没有差异。
FC-1271a对阴道的雌激素作用的评估
以下表1表示在各种剂量的FC-1271a或雷洛昔芬的给药3个月后基底旁细胞(MI 1)的成熟指数和表面细胞(MI 3)的成熟指数的改变
表1.在各种剂量的FC-1271a或雷洛昔芬的给药3个月后基底旁细胞(MI 1)的成熟指数和表面细胞(MI 3)的成熟指数的改变(MI 1：指数100，无雌激素性；指数0，完全的雌激素，MI 3：指数100，完全的雌激素；指数0，无雌激素性)
| 化合物和剂量 | MI 1平均值 | MI 1Sd | MI 3平均值 | MI 3 15sd |
| FC-1271a，30mg，(n＝21) | -40 | 42 | +12.4 | 13.6 |
| FC-1271a，60mg，(n＝20) | -26 | 39 | +5.5 | 13.4 |
| FC-1271a，90mg，(n＝22) | -48 | 44 | +12.5 | 14.0 |
| 雷洛昔芬，60mg，(n＝19) | -2 | 34 | -0.3 | 4.1 |
在图1A-1D中，用30mg FC-1271a(1A)，60mg FC-1271a(1B)，90mg FC-1271a(1C)，和60mg雷洛昔芬(1D)进行每日治疗的个体的阴道上皮表面细胞的核固缩指数表现出改变(从开始至12周的治疗)。
宫颈涂片检查表明雷洛昔芬组中没有人表现出在表面细胞核固缩指数方面从基线至治疗后的显著改变(图1D)。FC-1271a组中的大多数个体的该指数具有轻微的增加，但在其它个体中雌激素作用即使能测量到，也是非常微弱的。在所有病例中，与雌二醇相比，增加非常少(＜40，除90mg组中有一例为45)，已知雌二醇几乎使该指数增加100倍。因此在子宫颈涂片检查中记录了微弱但统计学显著的雌激素作用。在任何样品中没有病理学改变。
图2表示雷洛昔芬仅仅导致阴道干燥的微弱改变，这是由个体的主观估计而评价的，而所有FC-1271a剂量水平表现出明确的减少作用。每日60mg的FC-1271a产生最佳结果。
对FC-1271a的子宫内膜雌激素作用的评估
FC-1271a对子宫内膜组织学具有弱雌激素作用。该作用明显弱于在雌激素替代疗法中观察到的作用。在子宫内膜没有恶变的表现。在30、60和90mg组，通过超声评估的子宫内膜厚度仅仅分别表现出微小的、统计学上不显著的厚度增加(平均0.2mm、0.5mm和0.5mm)。测量值总是小于8mm，8mm被认为是表示他莫昔芬等抗雌激素药物的生理学显著的雌激素性的厚度(Hann et al，1997；Lahti et al，1993)。
对性活动的作用
在临床研究中，研究了FC-1271a对生活质量和心血管参数的作用，询问了患者的性活动。问卷包括对性活动的“恶化”或“无作用”。没有询问对性活动的改善。对70名患者进行了6周随访，其中的27名向研究者主动报道了性活动增加。从研究的不同中心也独立获得了相似的报道。这强烈表示FC-1271a对性活动和生活质量具有正作用。
这些结果表明，在对阴道干燥的雌激素样作用和不显著的子宫内膜作用方面，FC-1271a具有独特的药理学特征。在此临床研究中，FC-1271a对阴道和子宫具有微弱的雌激素样活性。在这些组织中，雌激素性显著低于已知的抗雌激素药物他莫昔芬和托米芬，但高于雷洛昔芬。与其它抗雌激素药物相反，它没有导致绝经症状。实际上剂量为每日25mg或更多，尤其是每日30-90mg的FC-1271a缓解这些症状。FC-1271a具有尤其有益的作用，它减少阴道干燥和性功能障碍。根据目前的数据，预计最优的临床剂量为高于每日25mg，低于每日100mg。特别优选的每日剂量为30-90mg。在更高的剂量(每日100和200mg)，FC-1271a表现出更多的雌激素样特征，其作用几乎类似于他莫昔芬和托米芬。由于FC-1271a的耐受性极佳，它是一种特别有价值的药物。此外，FC-1271a降低总胆固醇和LDL胆固醇，增加HDL胆固醇，并预防骨质疏松和早期乳腺癌。本发明表明，FC-1271a也可以在绝经期中代替雌激素用作雌激素替代疗法，已知雌激素增加乳腺癌和子宫内膜癌的风险。
应该理解本发明的方法是以各种实施方案的形式引入的，在此只公开了很少一部分。对于本领域的技术人员能够明白，存在其它实施方案并且不离开本发明的精神。因此，所描述的实施方案是说明性的，不应该解释为限制性的。
参考文献Delmas PD，Bjarnason NH，Mitlak BH，Ravoux AC，Shah AS，Huster WJ，Draper M，Christiansen C：Effects ofraloxifene on bone mineral density，serum cholesterol concentrations，and uterine endometrium inpostmenopausal women.N Engl J Med 337：1641-1647，1997Ettinger B，Genant HK，Cann CE：Long-term estrogen replacement therapyprevents bone loss and fractures.Ann Intern Med 102：319-324，1985Hann LE，Giess CS，Bach AM，Tao Y，Baum HJ，Barakat RR：Endometrialthickness in tamoxifen-treated patients：correlation with clinical andpathologic findings. Am J Roentgenol 168：657-661，1997Gustafsson J-：Estrogen receptor β-getting in on the action？NatureMedicine 3：493-494，1997Kangas L：Biochemical and pharmacological effects of toremifenemetabolites.Cancer Chemother Pharmacol 27：8-12，1990Kauffman RF，Bryant HU：Selective estrogen receptor modulators.DrugNews Perspeet 8：531-539，1995Lahti E，Blanco G，Kauppila A，Apaja-Sarkkinen M，Taskinen PJ，Laatikainen T：Endometrial changes in postmenopausal breast cancer patientsreceiving tamoxifen.Obstet Gynecol 81：660-664，1993Palkowitz AD，Glasebrook AL，Thraser KJ，Hauser KL，Short LL，PhillipsDL，Muchi BS，Sato M，Shetler PK，Cullinan GJ，Pell TR，BryantHU：Discovery and synthesis of [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene：anovel，highly potent，selective estrogen receptor modulator.Med Chem 40：1407-1416，1997Payer L：The menopause in various cultures.In：A portrait of the menopause.Expert reports on medical and therapeutic strategies for the 1990s.Ed.BurgerH & Boulet M，Parthenon Publishing，Park Ridge，NJ，USA，1991.pp 3-22Rekers H：Matering the menopause.In：A portrait of the menopause.Expertreports on medical and therapeutic strategies for the 1990s.Ed.Burger H &Boulet M，Parthenon Publishing，Park Ridge，NJ，USA，1991.pp 23-43Schneider LS，Finch CE：Can estrogens prevent neurodegeneration. Drugs &Aging 11：87-95，1997Spector IP，Carey MP：Incidence and prevalence of sexual dysfunctions：acritical review of the empirical literature.Archives of Sexual Behaviour 19：389-408，1990.Vuopala S，Kauppila A，Mikkonen M，Stenbck F：Screening ofasymptomatic postmenopausal women for gynecological malignancies，withspecial reference to endometrial sampling methods.Arch Gyncol 231：119-127，1982Wakeling AE，Bowler J：Biology and mode of action of pure antiestrogens.JSteroid Biochem 30：1-6，1988Wickelgren I：Estrogen stakes claim to cognition.Science 276：675-678，1997
Claims (8)
1.一种治疗绝经期或绝经后妇女阴道干燥或性功能障碍的方法，所述方法包括给予妇女有效量的化合物(脱氨基羟基)托米芬或其可药用盐或酯或其代谢物。
2.根据权利要求1的方法，其中该化合物或其盐或酯以每日25-100mg的剂量给药。
3.根据权利要求2的方法，其中该化合物或其盐或酯以每日30-90mg的剂量给药。
4.根据权利要求1-3的任意一项的方法，其中该化合物或其盐或酯是以口服或经皮给药。
5.化合物(脱氨基羟基)托米芬或其可药用盐或酯或其代谢物在制造用于治疗绝经期或绝经后妇女阴道干燥或性功能障碍的药物中的用途。
6.根据权利要求5的用途，其中该化合物或其盐或酯以每日25-100mg的剂量给药。
7.根据权利要求6的用途，其中该化合物或其盐或酯以每日30-90mg的剂量给药。
8.根据权利要求5-7的任意一项的用途，其中该化合物或其盐或酯是以口服或经皮给药。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/625,199 | 2000-07-21 | ||
| US09/625,199 US6245819B1 (en) | 2000-07-21 | 2000-07-21 | Method for the treatment of vaginal dryness and sexual dysfunction in women during or after the menopause |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1446085A true CN1446085A (zh) | 2003-10-01 |
| CN1287775C CN1287775C (zh) | 2006-12-06 |
Family
ID=24504996
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB018130194A Expired - Lifetime CN1287775C (zh) | 2000-07-21 | 2001-05-02 | 治疗绝经期或绝经后妇女更年期紊乱的方法 |
Country Status (31)
| Country | Link |
|---|---|
| US (5) | US6245819B1 (zh) |
| EP (1) | EP1305014B1 (zh) |
| JP (2) | JP5575351B2 (zh) |
| KR (1) | KR100880564B1 (zh) |
| CN (1) | CN1287775C (zh) |
| AT (1) | ATE300289T1 (zh) |
| AU (2) | AU2001258449B2 (zh) |
| BG (1) | BG65943B1 (zh) |
| BR (1) | BR0112659A (zh) |
| CA (1) | CA2416480C (zh) |
| CY (1) | CY1105370T1 (zh) |
| CZ (1) | CZ299439B6 (zh) |
| DE (1) | DE60112301T2 (zh) |
| DK (1) | DK1305014T3 (zh) |
| EE (1) | EE05344B1 (zh) |
| ES (1) | ES2241819T3 (zh) |
| HK (1) | HK1056694A1 (zh) |
| HR (1) | HRP20030024A2 (zh) |
| HU (1) | HU229361B1 (zh) |
| IL (1) | IL153823A (zh) |
| MX (1) | MXPA03000378A (zh) |
| NO (1) | NO329954B1 (zh) |
| NZ (1) | NZ524181A (zh) |
| PL (1) | PL202654B1 (zh) |
| PT (1) | PT1305014E (zh) |
| RU (1) | RU2268035C2 (zh) |
| SI (1) | SI1305014T1 (zh) |
| SK (1) | SK287096B6 (zh) |
| UA (1) | UA74386C2 (zh) |
| WO (1) | WO2002007718A1 (zh) |
| ZA (1) | ZA200300342B (zh) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1953741B (zh) * | 2004-02-23 | 2011-03-30 | 霍尔莫斯医疗有限公司 | 欧司哌米芬的固体制剂 |
| US8758821B2 (en) | 2004-05-04 | 2014-06-24 | Hormos Medical Ltd. | Oral formulations of ospemifene |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL120266A (en) | 1996-02-28 | 2005-05-17 | Pfizer | Use of estrogen antagonists and estrogen agonists in the preparation of medicaments for inhibiting pathological conditions |
| US20020013327A1 (en) * | 2000-04-18 | 2002-01-31 | Lee Andrew G. | Compositions and methods for treating female sexual dysfunction |
| DE60131644T2 (de) | 2000-05-09 | 2008-10-30 | Nitromed, Inc., Lexington | Infrarotthermographie und behandlung von sexuellen dysfunktionen |
| US6245819B1 (en) * | 2000-07-21 | 2001-06-12 | Hormos Medical Oy, Ltd. | Method for the treatment of vaginal dryness and sexual dysfunction in women during or after the menopause |
| EP1509215B1 (en) * | 2002-06-06 | 2006-11-02 | Hormos Medical Ltd. | Treatment or prevention of urogenital atrophy and its symptoms in women |
| US20060004088A1 (en) * | 2002-10-22 | 2006-01-05 | Oct Inc. | Furan derivatives for preventing and curing osteoporosis and pharmaceutical compositions containing the same |
| US20040248989A1 (en) | 2003-06-05 | 2004-12-09 | Risto Santti | Method for the treatment or prevention of lower urinary tract symptoms |
| US8236861B2 (en) | 2004-02-13 | 2012-08-07 | Hormos Medical Corporation | Method for enhancing the bioavailablity of ospemifene |
| US20050187302A1 (en) * | 2004-02-23 | 2005-08-25 | Hormos Medical Corporation | Method for treatment or prevention of osteoporosis in individuals with high bone turnover |
| ES2392344T3 (es) * | 2004-05-04 | 2012-12-07 | Hormos Medical Ltd. | Formulaciones orales líquidas de ospemifeno |
| KR100734942B1 (ko) | 2007-01-02 | 2007-07-03 | 김재현 | 여성 갱년기 증후군에 유효한 건강기능식품 조성물 |
| US7504530B2 (en) * | 2007-02-14 | 2009-03-17 | Hormos Medical Ltd. | Methods for the preparation of fispemifene from ospemifene |
| EP2121553B1 (en) * | 2007-02-14 | 2012-06-27 | Hormos Medical Ltd. | Method for the preparation of therapeutically valuable triphenylbutene derivatives |
| US20080293683A1 (en) * | 2007-05-24 | 2008-11-27 | University Of Kansas Medical Center | Hormone Replacement Therapy |
| RU2535112C2 (ru) * | 2012-09-19 | 2014-12-10 | Государственное бюджетное образовательное учреждение высшего профессионального образования "Дагестанская государственная медицинская академия министерства здравоохранения и социального развития" | Способ лечения климактерических и урогенитальных расстройств у женщин в постменопаузе на фоне гипотириоза |
| JP6174156B2 (ja) | 2012-10-19 | 2017-08-02 | フェルミオン オサケ ユキチュア | オスペミフェンの製造方法 |
| RU2694832C2 (ru) | 2015-03-10 | 2019-07-17 | Шионоги Инк. | Твёрдые дисперсии |
| US9750716B2 (en) | 2015-03-19 | 2017-09-05 | Wendy Anne Epstein | Compounds and forms of treatment for female sexual disorders |
| RU2636619C1 (ru) * | 2017-02-20 | 2017-11-24 | Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр акушерства, гинекологии и перинатологии имени академика В.И. Кулакова" Министерства здравоохранения Российской Федерации | Способ лечения вагинальной атрофии у женщин в постменопаузе с учетом состояния эпителия и микробиоценоза влагалища |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5352699A (en) | 1992-04-30 | 1994-10-04 | University Of Massachusetts Medical Center | Use of retinioc acid to treat vaginal atrophy |
| US5461064A (en) * | 1993-12-21 | 1995-10-24 | Eli Lilly And Company | Methods of inhibiting atrophy of the skin and vagina |
| GB9418067D0 (en) | 1994-09-07 | 1994-10-26 | Orion Yhtymae Oy | Triphenylethylenes for the prevention and treatment of osteoporosis |
| US5747059A (en) | 1996-01-11 | 1998-05-05 | Novo Nordisk A/S | Atrophy of skin/mucous membrane |
| GB9604577D0 (en) * | 1996-03-04 | 1996-05-01 | Orion Yhtymae Oy | Serum cholesterol lowering agent |
| CO5271697A1 (es) * | 2000-01-12 | 2003-04-30 | Pfizer Prod Inc | Composiciones y procedimientos para el tratamiento de afecciones que responden a un aumento de testosterona |
| KR20020073566A (ko) | 2000-01-28 | 2002-09-27 | 앙도르쉐르슈 인코포레이티드 | 에스트로겐과 배합된 선택적인 에스트로겐 수용체 조절자 |
| US20010034340A1 (en) | 2000-03-20 | 2001-10-25 | American Home Products Corporation | Hormone replacement therapy |
| US6245819B1 (en) | 2000-07-21 | 2001-06-12 | Hormos Medical Oy, Ltd. | Method for the treatment of vaginal dryness and sexual dysfunction in women during or after the menopause |
-
2000
- 2000-07-21 US US09/625,199 patent/US6245819B1/en active Active
-
2001
- 2001-02-05 UA UA2003021522A patent/UA74386C2/uk unknown
- 2001-05-02 AU AU2001258449A patent/AU2001258449B2/en not_active Expired
- 2001-05-02 SK SK1607-2002A patent/SK287096B6/sk not_active IP Right Cessation
- 2001-05-02 NZ NZ524181A patent/NZ524181A/en not_active IP Right Cessation
- 2001-05-02 PT PT01931746T patent/PT1305014E/pt unknown
- 2001-05-02 EP EP01931746A patent/EP1305014B1/en not_active Expired - Lifetime
- 2001-05-02 EE EEP200300031A patent/EE05344B1/xx unknown
- 2001-05-02 ES ES01931746T patent/ES2241819T3/es not_active Expired - Lifetime
- 2001-05-02 WO PCT/FI2001/000414 patent/WO2002007718A1/en active IP Right Grant
- 2001-05-02 JP JP2002513454A patent/JP5575351B2/ja not_active Expired - Lifetime
- 2001-05-02 CZ CZ20030026A patent/CZ299439B6/cs not_active IP Right Cessation
- 2001-05-02 IL IL153823A patent/IL153823A/en active IP Right Grant
- 2001-05-02 HU HU0301791A patent/HU229361B1/hu unknown
- 2001-05-02 AU AU5844901A patent/AU5844901A/xx active Pending
- 2001-05-02 BR BR0112659-8A patent/BR0112659A/pt not_active Application Discontinuation
- 2001-05-02 DE DE60112301T patent/DE60112301T2/de not_active Expired - Lifetime
- 2001-05-02 CA CA002416480A patent/CA2416480C/en not_active Expired - Lifetime
- 2001-05-02 AT AT01931746T patent/ATE300289T1/de active
- 2001-05-02 SI SI200130410T patent/SI1305014T1/sl unknown
- 2001-05-02 DK DK01931746T patent/DK1305014T3/da active
- 2001-05-02 PL PL359506A patent/PL202654B1/pl unknown
- 2001-05-02 KR KR1020027015576A patent/KR100880564B1/ko active IP Right Grant
- 2001-05-02 MX MXPA03000378A patent/MXPA03000378A/es active IP Right Grant
- 2001-05-02 CN CNB018130194A patent/CN1287775C/zh not_active Expired - Lifetime
- 2001-05-02 RU RU2003105159/14A patent/RU2268035C2/ru active
-
2002
- 2002-06-06 US US10/162,708 patent/US6984665B2/en not_active Expired - Lifetime
-
2003
- 2003-01-13 ZA ZA200300342A patent/ZA200300342B/en unknown
- 2003-01-17 HR HR20030024A patent/HRP20030024A2/xx not_active Application Discontinuation
- 2003-01-17 BG BG107472A patent/BG65943B1/bg unknown
- 2003-01-20 NO NO20030273A patent/NO329954B1/no not_active IP Right Cessation
- 2003-12-17 HK HK03109192A patent/HK1056694A1/xx not_active IP Right Cessation
-
2005
- 2005-08-11 US US11/201,098 patent/US20050272825A1/en not_active Abandoned
- 2005-10-26 CY CY20051101313T patent/CY1105370T1/el unknown
-
2010
- 2010-07-15 US US12/837,292 patent/US9566252B2/en not_active Expired - Lifetime
-
2012
- 2012-10-25 JP JP2012235543A patent/JP5629746B2/ja not_active Expired - Lifetime
-
2014
- 2014-01-24 US US14/163,757 patent/US20140142195A1/en not_active Abandoned
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1953741B (zh) * | 2004-02-23 | 2011-03-30 | 霍尔莫斯医疗有限公司 | 欧司哌米芬的固体制剂 |
| US8758821B2 (en) | 2004-05-04 | 2014-06-24 | Hormos Medical Ltd. | Oral formulations of ospemifene |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1287775C (zh) | 治疗绝经期或绝经后妇女更年期紊乱的方法 | |
| AU2001258449A1 (en) | Method for the treatment of climacteric disorders in women during or after the menopause | |
| NO336612B1 (no) | Anvendelse av en forbindelse for fremstilling av en farmasøytisk sammensetning for hemming av urininkontinens i en kvinne |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CX01 | Expiry of patent term | ||
| CX01 | Expiry of patent term |
Granted publication date: 20061206 |